Progress during past year: Disease mechanisms in zaspopathy, a prototype myofibrillar myopathy: We completed initial characterization of functional interactions of ZASP with skeletal muscle actin monomers and filaments (published). Our results indicate that ZASP interactions with skeletal muscle actin play a fundamental role in the disease mechanism of zaspopathy. Next steps are to examine the role of ZASP-actin interaction in vivo in disease model systems (knock in mice, transgenic fish, stable inducible muscle cell lines). To this regard, stable inducible muscle cell lines have been generated and are now characterized for the actin phenotype. Transgenic fish lines have been generated and are now bred to expand the lines. Knock in targeting constructs are finally made after rigorous efforts. We have tested and validated screening protocols of knock in recombination. In addition, we have initiated studies to determine the structure of ZASP-actin complex (collaboration with Wingfield and Steven laboratories). It took a significant effort to purify ZASP proteins (His6 tagged and untagged) (collaboration with Wingfield laboratory, NIAMS). We have determined the binding affinities of ZASP to skeletal muscle actin by surface plasmon resonance assay and measured stoichiometry of ZASP-actin interaction. Efforts are underway to crystallize ZASP proteins. We have begun studies to examine ZASP-actin protein complex with cryo-electron microscope. Patient studies: We have initiated annual follow up evaluations of family members of the original zaspopathy pedigree to characterize natural history of the disease. We completed enrollment of subjects (n=33) to the DMD Imaging Biomarker study (protocol ID 11-N-0261). Data analysis is ongoing and is in the final phases. Clinical observations in one of the research subjects were published (see below). We have started enrolling patients into the Myotonic Dystrophy Biomarker study (protocol 14-N-0132). We have identified novel gene defects and known gene mutations in several of our patients including the ones in the Neurogenetics clinic by using NextGen exome analysis. Efforts are underway to characterize the biological effects of the novel variants in cell systems and patient tissues.

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Todd, Joshua J; Razaqyar, Muslima S; Witherspoon, Jessica W et al. (2018) Novel Variants in Individuals with RYR1-Related Congenital Myopathies: Genetic, Laboratory, and Clinical Findings. Front Neurol 9:118
Jerath, Nivedita U; Mankodi, Ami; Crawford, Thomas O et al. (2018) Charcot-Marie-Tooth Disease type 4C: Novel mutations, clinical presentations, and diagnostic challenges. Muscle Nerve 57:749-755
Watts, Norman R; Zhuang, Xiaolei; Kaufman, Joshua D et al. (2017) Expression and Purification of ZASP Subdomains and Clinically Important Isoforms: High-Affinity Binding to G-Actin. Biochemistry 56:2061-2070
Kovacs, William; Hsieh, Nathan; Roth, Holger et al. (2017) Holistic segmentation of the lung in cine MRI. J Med Imaging (Bellingham) 4:041310
Mankodi, Ami; Kovacs, William; Norato, Gina et al. (2017) Respiratory magnetic resonance imaging biomarkers in Duchenne muscular dystrophy. Ann Clin Transl Neurol 4:655-662
Mankodi, Ami; Azzabou, Noura; Bulea, Thomas et al. (2017) Skeletal muscle water T2 as a biomarker of disease status and exercise effects in patients with Duchenne muscular dystrophy. Neuromuscul Disord 27:705-714
Gaur, Lasya; Hanna, Alexander; Bandettini, W Patricia et al. (2016) Upper arm and cardiac magnetic resonance imaging in Duchenne muscular dystrophy. Ann Clin Transl Neurol 3:948-955
Mankodi, Ami; Bishop, Courtney A; Auh, Sungyoung et al. (2016) Quantifying disease activity in fatty-infiltrated skeletal muscle by IDEAL-CPMG in Duchenne muscular dystrophy. Neuromuscul Disord 26:650-658
Mankodi, Ami; Grunseich, Christopher; Skov, Martin et al. (2015) Divalent cation-responsive myotonia and muscle paralysis in skeletal muscle sodium channelopathy. Neuromuscul Disord 25:908-12
Mankodi, Ami; Grunseich, Christopher (2015) Toe-extension myotonia in myotonic dystrophy type 1. Neurology 85:203

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